WO2017205585A1 - Combinaisons, utilisations et traitements correspondants - Google Patents

Combinaisons, utilisations et traitements correspondants Download PDF

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WO2017205585A1
WO2017205585A1 PCT/US2017/034404 US2017034404W WO2017205585A1 WO 2017205585 A1 WO2017205585 A1 WO 2017205585A1 US 2017034404 W US2017034404 W US 2017034404W WO 2017205585 A1 WO2017205585 A1 WO 2017205585A1
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compound
formula
hiv
pharmaceutical composition
administered
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PCT/US2017/034404
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English (en)
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William R. SPREEN
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Viiv Healthcare Company
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/66—Phosphorus compounds
    • A61K31/675—Phosphorus compounds having nitrogen as a ring hetero atom, e.g. pyridoxal phosphate
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/4985—Pyrazines or piperazines ortho- or peri-condensed with heterocyclic ring systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim

Definitions

  • TAF Tenofovir alafenamide
  • TAF is a nucleotide reverse transcriptase inhibitor and is currently under development for the treatment and prevention of HIV. TAF has been reported to have greater antiviral activity and a lower incidence of adverse side effects when compared to tenofovir disoproxil.
  • Cabotegravir is an integrase inhibitor that is currently in the clinic for the treatment of HIV infection.
  • Rilpivirine (TMC278) is a diarylpyrimidine (DAPY) second-generation non-nucleoside reverse transcriptase inhibitor (NNRTI) currently in clinical trials for the treatment of HIV infection and is approved and marketed in some countries under the trade name,
  • One embodiment of the invention provides a method for treating or preventing HIV in a patient comprising administering to the patient a pharmaceutically effective amount of a compound of formula I:
  • the compound of formula I is in a pharmaceutical composition comprising the compound of formula I and fumarate.
  • the compound of formula I is in a pharmaceutical composition comprising the compound of formula I and fumaric acid.
  • the compound of formula II is in a pharmaceutical composition comprising the compound of formula II and sodium.
  • the compound of formula I and the compound of formula II are co-administered in separate dosage forms.
  • the compound of formula I and the compound of formula II are co-administered in a single dosage form.
  • the compound of formula I and the compound of formula II are orally co-administered.
  • the compound of formula II is in a pharmaceutical composition comprising the compound of formula II and sodium.
  • the compound of formula II and the compound of formula III are co-administered in a single dosage form.
  • the compound of formula I and the compound of formula III are co-administered in a single dosage form.
  • the compound of formula II, the compound of formula II, and the compound of Formula III are co-administered in a single dosage form.
  • the compound of formula I, the compound of formula II, and the compound of formula III are co-administered in separate dosage forms.
  • the compound of formula II and the compound of formula III are co-administered in a single dosage form, and the compound of formula I is co- administered separately.
  • the compound of formula II and the compound of formula III are orally co-administered.
  • the compound of formula I, the compound of formula II, and the compound of formula III are orally co-administered.
  • Another embodiment provides a pharmaceutically acceptable composition comprising:
  • Yet a further embodiment of the invention provides a method for treating or preventing HIV in a patient comprising administering to the patient a
  • the compound of formula III is in a pharmaceutical composition comprising the compound of formula III and hydrochloride.
  • the compound of formula I, the compound of formula II, and the compound of formula III are co-administered in separate dosage forms.
  • the compound of formula I, the compound of formula II, and the compound of formula III are co-administered in separate dosage forms, wherein the compound of formula I is in an oral form, the compound of formula II is in a parenteral form, and the compound of formula III is in a parenteral form.
  • the compound of formula I, the compound of formula II, and the compound of formula III are co-administered in a single dosage form.
  • the compound of formula I, the compound of formula II, and the compound of formula III are co-administered.
  • any two compounds selected from the compound of formula I, the compound of formula II, and the compound of formula III are co- administered in a single dosage form with the remaining compound in a separate dosage form.
  • a method for treating or preventing an HIV infection in a human having or at risk of having the infection comprising administering to the human a therapeutically effective amount of cabotegravir and tenofovir alafenamide, or a pharmaceutical composition thereof, in combination with a therapeutically effective amount of one or more (e.g., one, two, three, one or two, or one to three) additional therapeutic agents.
  • the present disclosure provides a method for treating an HIV infection, comprising administering to a patient in need thereof a
  • cabotegravir and tenofovir alafenamide or a pharmaceutically acceptable composition thereof, in combination with a
  • compositions comprising cabotegravir and tenofovir alafenamide, in combination with one or more (e.g., one, two, three, one or two, or one to three) additional therapeutic agents, and a pharmaceutically acceptable carrier, diluent or excipient are provided.
  • kits comprising cabotegravir and tenofovir alafenamide, or a pharmaceutical composition thereof, in combination with one or more (e.g., one, two, three, one or two, or one to three) additional therapeutic agents are provided.
  • a method for treating or preventing an HIV infection in a human having or at risk of having the infection comprising administering to the human a therapeutically effective amount of cabotegravir, tenofovir alafenamide, and rilpivirine, or a pharmaceutical composition thereof, in combination with a therapeutically effective amount of one or more (e.g., one, two, three, one or two, or one to three) additional therapeutic agents.
  • the present disclosure provides a method for treating an HIV infection, comprising administering to a patient in need thereof a
  • compositions comprising cabotegravir, tenofovir alafenamide, and rilpivirine in combination with one or more (e.g., one, two, three, one or two, or one to three) additional therapeutic agents, and a pharmaceutically acceptable carrier, diluent or excipient are provided.
  • kits comprising cabotegravir, tenofovir alafenamide, and rilpivirine, or a pharmaceutical composition thereof, in combination with one or more (e.g., one, two, three, one or two, or one to three) additional therapeutic agents are provided.
  • kits comprising cabotegravir, tenofovir alafenamide, and rilpivirine, or a pharmaceutical composition thereof, in oral and/or parenteral dosage forms are provided.
  • Certain such kits comprise tenofovir alafenamide in tablet dosage form, cabotegravir in a syringe dosage form, and rilpivirine in a syringe dosage form.
  • the additional therapeutic agent may be an anti-HIV agent.
  • the additional therapeutic agent is chosen f rom: HIV protease inhibitors, HIV non-nucleoside or non-nucleotide inhibitors of reverse tran- scriptase, HIV nucleoside or nucleotide inhibitors of reverse transcriptase, HIV integrase inhibitors, HIV non-catalytic site (or allosteric) integrase inhibitors, HIV entry inhibitors (e.g., CCR5 inhibitors, gp41 inhibitors (i.e., fusion inhibitors) and CD4 attachment inhibitors), CXCR4 inhibitors, gp120 inhibitors, G6PD and NADH-oxidase inhibitors, HIV vaccines, HIV maturation inhibitors, latency reversing agents (e.g., histone deacetylase inhibitors, proteasome inhibitors, protein kinase C (PKC) activators, and BRD4 inhibitors), compounds
  • PLC protein kinase C
  • the additional therapeutic chosen from: HIV protease inhibitors, HIV non-nucleoside or non-nucleotide inhibitors of reverse transcriptase, HIV nucleoside or nucleotide inhibitors of reverse transcriptase, HIV integrase inhibitors, HIV non-catalytic site (or allosteric) integrase inhibitors, pharmacokinetic enhancers, and combinations thereof.
  • tenofovir alafenamide and cabotegravir are formulated as a tablet that may optionally contain one or more other compounds useful for treating HIV.
  • the tablet can contain another active ingredient for treating HIV, such as HIV protease inhibitors, HIV non-nucleoside or non-nucleotide inhibitors of reverse transcriptase, HIV nucleoside or nucleotide inhibitors of reverse transcriptase, HIV integrase inhibitors, HIV non-catalytic site (or allosteric) integrase inhibitors, pharmacoki- netic enhancers, and combinations thereof.
  • such tablets are suitable for once daily dosing.
  • the additional therapeutic agent may be chosen from one or more of:
  • Combination drugs chosen from: ATRIPLA ® (efavirenz+tenofovir disoproxil fumarate+emtricitabine ), COMPLERA ® (EVIPLERA ® , rilpivirine+tenofovir disoproxil fumarate+emtricitabine ), STRIBILD ® (elvitegravir+cobicistat+tenofovir disoproxil fumarate+emtricitabine), lamivudine+nevirapine+zidovu dine, atazanavir
  • TRIZIVIR ® abacavir sulfate+zidovudine+ lamivudine, ABC+AZT+3TC
  • TRUVADA ® tenofovir disoproxil fumarate+emtricitabine
  • HIV protease inhibitors chosen f rom: amprenavir, atazanavir, fosamprenavir, fosam- prenavir calcium, indinavir, indinavir sulfate, lopinavir, ritonavir, nelfinavir, nelfinavir mesylate, saquinavir, saquinavir mesylate, tipranavir, brecanavir, darunavir, DG-17, TMB-657 (PPL-100), TMC-310911, and TMB-657; (3) HIV non-nucleo
  • HIV integrase inhibitors chosen from: curcumin, derivatives of curcumin, chicoric acid, derivatives of chicoric acid, 3,5-dicaffeoylquinic acid, derivatives of 3,5-dicaffeoylquinic acid, aurintricarboxylic acid, derivatives of aurintricarboxylic acid, caffeic acid phen- ethyl ester, derivatives of caffeic acid phenethyl ester, tyrphostin, derivatives of tyrphostin, quercetin, derivatives of quercetin, raltegravir, a n d TIVICAY ® (dolutegravir); (6) HIV non-catalytic site, or allosteric, integrase inhibitors (NCINI) chosen from: CX-05168, CX-05045 and CX-14442; (7) HIV gp41 inhibitors chosen from: enfuvirtide, sifuvirtide and alb
  • Tatlmmune GTU-multi-HIV (FIT-06), AGS-004, gp140[delta]V2.TVI+MF-59, rVSVIN HIV-1 gag vaccine, SeV-Gag vaccine, AT-20, DNK-4, Ad35-GRIN/ENV, TBC-M4, HIVAX, HIVAX-2, NYVAC-HIV-PTl, NYVAC-HIV-PT4, DNA-HIV- PT123, VIChREPOL ® , rAAV1-PG9DP, GOVX-Bl l, GOVX-B21, ThV- 01, TUTI- 16, VGX-3300, TVI-HIV-1, Ad-4 (Ad4-env Clade C+Ad4-mGag), EN41-FPA2, PreVaxTat, TL-01, SAV-001, AE-H, MYM-VlOl, CombiHIVvac, ADVAX, MYM- V201, monomeric gp120 HIV
  • HIV antibodies, bispecific antibodies and "antibody-like" therapeutic proteins such as DARTs ® , Duo- bodies ® , Bites ® , XmAbs®, TandAbs ® , Fab derivatives
  • BMS-936559, TMB-360 and those targeting HIV gp120 or gp41 are chosen from: bavituximab, UB-421, C2F5, C2G12, C4E10, C2F5+C2G12+ C4E10, 3-BNC- 117, KD-247, PGT145, PGT121, MDXOlO (ipilimumab), VRCOl, A32, 7B2, 10E8, VRC-07-523 and VRC07; (17) latency reversing agents chosen from: histone
  • W02012/003497 (Gilead Sciences), W02014/100323 (Gilead Sciences), W02012/ 145728 (Gilead Sciences), W02013/159064 (Gilead Sciences) and WO 2012/003498 (Gilead Sciences); and (22) other drugs for treating HIV chosen from: REP 9, cytolin, CYT-107, alisporivir, BanLec, MK-8507, AG-1105, TR-452, MK-8591, REP 9, NOV-205, IND-02, metenkefalin, PGN-007, Acemannan, Gamimune, SCY-635, prolastin, 1,5- dicaffeoylquinic acid, BIT-225, RPI-MN, VSSP, Hlviral, IM0-3100, SB-728-T, RPI- MN, VIR-576, HGTV-43, MK-1376, rHIV7-shl-TAR-CCR5RZ, MazF gene
  • the one, two, three, four or more additional therapeutic agents can be different therapeutic agents selected from the same class of therapeutic agents, and/or they can be selected from different classes of therapeutic agents.
  • cabotegravir tenofovir alafenamide, and rilpivirine, or a pharmaceutical composition thereof is combined with one, two, three, four or more additional therapeutic agents selected from raltegravir, Truvada ® (tenofovir disoproxil fumarate+emtricitabine, TDF+FTC), maraviroc, enfuvirtide, EPZICOM ® (LIVEXA ® , abacavir sulfate+lamivu- dine, ABC+3TC), TRIZIVIR ® (abacavir sulfate+zidovudine+ lamivudine,
  • raltegravir+lamivudine COMPLERA ® (EVIPLERA ® , rilpivirine+tenofovir disoproxil fumarate+emtricitabine ), Cobicistat, ATRIPLA ® (efavirenz+tenofovir disoproxil fumarate+emtricitabine ), atazanavir sulfate+cobicistat, atazanavir+cobicistat, darunavir+cobicistat, atazanavir, atazanavir sulfate, elvitegravir, ALUVIA ®
  • tenofovir alafenamide and cabotegravir or tenofovir
  • alafenamide, cabotegravir, and rilpivirine are administered with either emtricitabine or lamivudine.
  • cabotegravir and tenofovir are administered with either emtricitabine or lamivudine.
  • alafenamide, or tenofovir alafenamide, cabotegravir, and rilpivirine, or a pharmaceutical composition thereof is combined with one or more additional therapeutic agents as described above, the components of the composition are administered as a simultaneous or sequential regimen. When administered sequentially, either combination may be administered in two or more administrations.
  • cabotegravir and tenofovir alafenamide, or cabotegravir, tenofovir alafenamide, and rilpivirine, or a pharmaceutical composition thereof, a r e administered with one or more additional therapeutic agents generally refers to simultaneous or sequential administration of a compound disclosed herein and one or more additional therapeutic agents, such that therapeutically effective amounts of the compound disclosed herein and one or more additional therapeutic agents are both present in the body of the patient.
  • Co-administration includes administration of unit dosages of cabotegravir and tenofovir alafenamide, or cabotegravir, tenofovir alafenamide, and rilpivirine, or a pharmaceutical composition thereof, before or after administration of unit dosages of one or more additional therapeutic agents, for example, administration of cabotegravir and tenofovir alafenamide, or cabotegravir, tenofovir alafenamide, and rilpivirine or a pharmaceutical composition thereof, within seconds, minutes, or hours of the administration of one or more additional therapeutic agents.
  • a unit dose of cabotegravir and tenofovir alafenamide, or cabotegravir, tenofovir alafenamide, and rilpivirine, or a pharmaceutical composition thereof is administered first, followed within seconds or minutes by administration of a unit dose of one or more additional therapeutic agents.
  • a unit dose of one or more additional therapeutic agents is administered first, followed within seconds or minutes by administration of a unit dose of one or more additional therapeutic agents.
  • a unit dose of one or more additional therapeutic agents is administered first, followed by administration of a unit dose of cabotegravir and tenofovir alafenamide, or cabotegravir, tenofovir alafenamide, rilpivirine, or a pharmaceutical composition thereof, within seconds or minutes.
  • cabotegravir, tenofovir alafenamide, and rilpivirine, or a pharmaceutical composition thereof is administered first, followed, after a period of hours (e.g., 1-12 hours), by administration of a unit dose of one or more additional therapeutic agents.
  • a unit dose of one or more additional therapeutic agents is
  • cabotegravir and tenofovir alafenamide are administered orally.
  • the combination of cabotegravir and tenofovir alafenamide is administered to the patient once a day.
  • the combination of cabotegravir and tenofovir alafenamide is administered to the patient twice a day.
  • c a b o t egravir is administered to the patient at about 25 mg, about 30 mg, about 35 mg, about 40 mg, about 45 mg dose, about 50 mg, about 55 mg, about 60 mg, about 65 mg, about 70 mg, about 75 mg, about 80 mg, about 85 mg, about 90 mg, about 95 mg or about 100 mg, once, twice or three times a day.
  • cabotegravir is administered to the patient at about 25 mg to 100 mg, at about 25 mg to 75 mg, at about 35 mg to 65 mg or about 45 mg to 55 mg, once or twice per day.
  • cabotegravir is administered to the patient at about 50 mg, once or twice per day.
  • tenofovir alafenamide is administered to the patient at about 1 mg, about 5 mg, about 10mg, about 15mg, about 20 mg, about 25 mg dose, about 30 mg, about 35 mg, about 40 mg, about 45 mg or about 50 mg once, twice or three times a day.
  • tenofovir alafenamide is administered to the patient at about 1 mg to 50 mg or at about 5 mg to 25 mg once per day.
  • tenofovir alafenamide is administered to the patient at about 5 mg, once per day.
  • tenofovir alafenamide is administered to the patient at about 10mg, once per day.
  • tenofovir alafenamide is administered to the patient at about 25 mg, once per day.
  • cabotegravir, tenofovir alafenamide, rilpivirine, or a pharmaceutical composition thereof are administered orally.
  • the combination of cabotegravir, tenofovir alafenamide, and rilpivirine is administered to the patient once a day.
  • the combination of cabotegravir, tenofovir alafenamide, and rilpivirine is administered to the patient twice a day.
  • rilpivirine is administered to the patient as a tablet, wherein the effective amount is: between 1 to 1000 mg of active ingredient per unit dosage form; between 5 and 200 mg of active ingredient per unit dosage form; between 1 to 1000 mg of active ingredient; or between 5 to 200 mg of active ingredient.
  • ril p i v i r i n e is administered to the patient in a tablet form at about 25 mg., once per day.
  • co-administer refers to administration of two or more agents within a 24-hour period of each other, for example, as part of a clinical treatment regimen. In other embodiments, “co-administer” refers to administration of two or more agents within 2 hours of each other. In other embodiments, “co-administer” refers to administration of two or more agents within 30 minutes of each other. In other embodiments, “co-administer” refers to administration of two or more agents within 15 minutes of each other. In other embodiments, “co-administer” refers to administration at the same time, either as part of a single formulation or as multiple formulations that are administered by the same or different routes.
  • TAF Tinofovir alafenamide
  • R ⁇ 9-[(R)-2- [[(S)-[[(S)-1- (isopropoxycarbonyl)ethyl]amino ]phenoxy- phosphinyl ]-methoxy]propyl]adenine ⁇ :
  • TAF may be associated with fumarate, such as monofumarate and hemifumarate.
  • Methods for preparing TAF are disclosed in US Patent 7,390,791.
  • TFV or Tenofovir is:
  • TDF may be associated with fumarate, such as monofumarate.
  • fumarate such as monofumarate.
  • Cabotegravir may be associated with sodium. Methods for preparing cabotegravir are described in US Patent 8,410,103. “Rilpivirine is:
  • Rilpivirine may be associated with hydrochloride. Methods for preparing rilpivirine are described in US Patent 7,125,879.
  • “Emtricitabine” or “FTC” refers to (2R,5S,cis)-4- amino-5-fluoro-l-(2-hydroxymethyl- 1,3-oxathiolan-5-yl)- (lH)-pyrimidin-2-one.
  • “Therapeutically effective amount” or “effective amount” refers to that amount of the compound being administered that will prevent a condition, or will relieve to some extent one or more of the symptoms of the disorder being treated.
  • Pharmaceutical compositions suitable for use herein include compositions wherein the active ingredients are contained in an amount sufficient to achieve the intended purpose.
  • treatment refers to inhibition, reduction, elimination or alleviation of a disease, as well as prevention.
  • Combinations and Methods of Treatment A method for the treatment or prophylaxis of diseases, disorders, and conditions is provided herein.
  • An example of a disease, disorder, or condition includes, but is not limited to, a retrovirus infection, or a disease, disorder, or condition associated with a retrovirus infection.
  • Retroviruses are RNA viruses and are generally classified into the alpharetrovirus, betaretrovirus, deltaretrovirus, epsilonretrovirus, gammaretrovirus, lentivirus, and spumavirus families.
  • retroviruses include, but are not limited to, human immunodeficiency virus (HIV).
  • the active agents of the disclosed combination therapy may be administered to a human in any conventional manner. While it is possible for the active agents to be administered as compounds, they are preferably administered as a pharmaceutical composition that can include contact with an acid or base, either in an ionic salt form or in contact with the base or acid (i.e., co-formers) without sharing ions.
  • the salt, acid or base co-former, carrier, or diluent should be acceptable, in the sense of being compatible with the other ingredients and not deleterious to the recipient thereof.
  • carriers or diluents for oral administration include, but are not limited to: cornstarch, lactose, magnesium stearate, talc, microcrystalline cellulose, stearic acid, povidone, crospovidone, dibasic calcium phosphate, sodium starch glycolate, hydroxypropyl cellulose (e.g., low substituted hydroxypropyl cellulose),
  • hydroxypropylmethyl cellulose e.g., hydroxypropylmethyl cellulose 2910
  • sodium lauryl sulfate mannitol
  • sodium stearyl fumarate sodium stearyl fumarate
  • salts and acid or base co-formers include fumarate, hemifumarate, sodium, and hydrochloride.
  • the pharmaceutical compositions may be prepared by any suitable method, such as those methods well known in the art of pharmacy, for example, methods such as those described in Gennaro, et al., REMINGTON'S PHARMACEUTICAL SCIENCES (18th ed., Mack Publishing Co., 1990), especially“Part 8: Pharmaceutical Preparations and their Manufacture”.
  • Such methods include the step of bringing into association the compounds with the carrier or diluents and, optionally, one or more accessory ingredients.
  • accessory ingredients include, but are not limited to: fillers, binders, excipients, disintegrants, lubricants, colorants, flavoring agents, sweeteners, preservatives (e.g., antimicrobial preservatives), suspending agents, thickening agents, emulsifying agents, and/or wetting agents.
  • the amount of each compound to be administered ranges from about 0.001 to 100 mg per kg of body weight, such total dose being given at one time or in divided doses.
  • Each compound will be administered as a formulation in association with one or more pharmaceutically acceptable excipients.
  • both compounds will be combined and administered as a formulation in association with one or more pharmaceutically acceptable excipients.
  • the choice of excipient will, to a large extent, depend u p on factors such as the particular mode of
  • Example 1 HIV Cell Line Assay The HIV cell line experiments taught by Kobayashi, et al., Antimicrobial Agents and Chemotherapy, 55: 814-815 (2011) are followed to test the antiviral abilities of two disclosed and claimed combinations: (1) TAF plus cabotegravir; and (2) TAF plus cabotegravir plus rilpivirine as compared with the antiviral abilities of each of these three compounds alone.
  • Compounds. TAF, cabotegravir, and rilpivirine are synthesized at GlaxoSmithKline ® , Research Triangle Park, NC. The structures of each of these compounds are shown above in formulas I, II, and II, respectively. Cells and viruses.
  • HTLV-1 human T-cell leukemia virus type 1
  • MT-4 a human T-cell leukemia virus type 1 (HTLV-1)- transformed human T-cell line
  • 293T cells are maintained in Dulbecco’s modified Eagle medium (DMEM)–F-12 medium containing 10% fetal bovine serum (FBS).
  • DMEM Dulbecco modified Eagle medium
  • FBS fetal bovine serum
  • PBMCs Peripheral blood mononuclear cells
  • PBMCs are separated from whole blood by density gradient centrifugation with Ficoll-Paque Plus ® (GE Healthcare ® , Waukesha, WI) according to the manufacturer’s instructions and are stimulated by the addition of either 20 U/ml of interleukin-2 (IL-2) or 10% natural T-cell growth factor (ZeptoMetrix ® , Buffalo, NY) plus 5 to 10 ⁇ g/ml of phytohemagglutinin (PHA).
  • IL-2 interleukin-2
  • ZeptoMetrix ® 10% natural T-cell growth factor
  • PHA phytohemagglutinin
  • Molt-4 cells persistently infected with HIV-1 IIIB and MT-2 cells [16] are obtained from S. Harada (Kumamoto University, Kumamoto, Japan).
  • HIV-1 strain IIIB is derived from cell-free supernatants of cultures of the chronically infected cell line, H93B (H9/HTLV-IIIB).
  • HIV-1 strain Ba-L is purchased from Advanced Biotechnologies Inc. ® (Columbia, MD) and i s expanded in PHA- activated PBMCs, while HIV-1 NL432 [1] is obtained from A. Adachi (Tokushima University, Tokushima, Japan).
  • Plasmid pGJ3-Luci containing a replication- defective HIV lentiviral vector expressing luciferase [21], is licensed from Christian Jassoy (University of Leipzig), and is used to create stocks of a vesicular stomatitis virus glycoprotein G (VSV-G)-pseudotyped self-inactivating pseudo-HIV (PHIV) lentiviral vector by cotransfection, along with plasmid pVSV-G (Clontech ® ) into CIP4 cells (a derivative of the 293T human renal epithelial cell line that expresses macrophage scavenger receptor SRA-I to improve adherence to plastic) and harvesting of the cell-free supernatant.
  • VSV-G vesicular stomatitis virus glycoprotein G
  • PIV pseudo-HIV
  • MT-4 cells growing exponentially at a density of 5 X 10 5 or 6 X 10 5 /ml are infected with HIV-1 strain IIIB at a viral multiplicity of infection of 0.001 or a 50% tissue culture infective dose of 4 to 10. The cells are then aliquoted to 96-well plates in the presence of varying concentrations of compounds.
  • antiviral activity is determined by a cell viability assay that either measures bioluminescence with a CellTiter-Glo ® luminescent reagent (Promega Corporation ® , Madison, WI) or measured absorbance at 560 and 690 nm using the yellow tetrazolium MTT reagent [3-(4,5- dimethyl-2- thiazolyl)-2,5-diphenyltetrazolium bromide]. Pseudo-HIV assay.
  • TAF, cabotegravir, and rilpivirine alone, as well as the combinations of: (1) TAF plus cabotegravir; and (2) TAF plus cabotegravir plus rilpivirine are measured in a single-round assay using a self- inactivating PHIV lentiviral vector.
  • CIP4 cells (2 X 10 4 /well) infected with an amount of PHIV sufficient to produce approximately 50,000 relative light units are added to 96-well black, clear-bottom plates and were incubated for 2 days with all three compounds at varying concentrations.
  • Infected cells are measured as a function of luciferase activity in a luminometer using the Steady-Glo ® reagent (Promega Corporation ® ).
  • Antiviral assay in PBMCs In one 96-well culture plate, PHA- and IL-2- stimulated PBMCs (4 X 10 5 /well) are pre-incubated with each compound alone, and then for each of the two above combinations of the compounds, for 1 h, while HIV-1 strain, Ba- L, is mixed with the same compound in a second plate. An aliquot of the Ba-L– compound mixture i s then transferred to the PBMC- compound mixture and is incubated for 7 days.
  • PA-EC 50 protein-adjusted half-maximal effective concentration
  • cabotegravir alone (1) cabotegravir alone; (2) TAF alone; (3) rilpivirine alone; (4) cabotegravir plus TAF; and (5) cabotegravir plus TAF plus rilpivirine are determined as previously described [39].
  • Multiple concentrations of the compounds are tested in checkerboard dilution fashion in the presence and absence of dilutions of approved anti-HIV drugs, adefovir, or ribavirin.
  • the assay used HIV-1 IIIB-infected MT-4 cells, and the interaction of compound combinations is analyzed by dose wise additivity-based calculations to quantify deviation from dose wise additivity at the 50% level.
  • anti-hepatitis B virus anti-HBV
  • anti-HCV agents adefovir and ribavirin on: (1) cabotegravir alone; (2) TAF alone; (3) rilpivirine alone; (4) TAF plus cabotegravir; and (5) TAF plus cabotegravir plus rilpivirine are examined using linear regression, as described previously [41].
  • the CCR5 inhibitor, maraviroc is evaluated in a checker- board dilution format using MAGI-CCR5 cells with the Gal Screen reagent (Tropix ® , Bedford, MA) for chemiluminescent endpoints, and data are analyzed as described by Prichard and Shipman [37] by using the MacSynergy II ® program. Synergy volumes in the range of -50 to 50 define additivity; ⁇ -50, antagonism; and >50, synergy.

Abstract

La présente invention concerne des procédés de traitement ou de prévention du VIH chez un patient à l'aide d'une combinaison de ténofovir alafénamide (TAF) et de cabotégravir, ainsi que des compositions contenant de tels composés.
PCT/US2017/034404 2016-05-27 2017-05-25 Combinaisons, utilisations et traitements correspondants WO2017205585A1 (fr)

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Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN109568328A (zh) * 2017-09-29 2019-04-05 重庆药友制药有限责任公司 一种用于预防和治疗hiv感染的药物组合物
WO2022003598A1 (fr) * 2020-07-02 2022-01-06 Viiv Healthcare Company Procédé d'obtention d'une rémission virale du vih à l'aide d'agents antirétroviraux à action prolongée
WO2022125378A3 (fr) * 2020-12-07 2022-07-21 Viiv Healthcare Company Polythérapie

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2011119566A1 (fr) * 2010-03-23 2011-09-29 Glaxosmithkline Llc Processus permettant de préparer des dérivés et des produits intermédiaires de carbamoylpyridone
US20150238496A1 (en) * 2010-01-27 2015-08-27 Viiv Healthcare Company Antiviral therapy
US20160067255A1 (en) * 2014-09-04 2016-03-10 Gilead Sciences, Inc. Methods of treating or preventing hiv in patients using a combination of tenofovir alafenamide and dolutegravir

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20150238496A1 (en) * 2010-01-27 2015-08-27 Viiv Healthcare Company Antiviral therapy
WO2011119566A1 (fr) * 2010-03-23 2011-09-29 Glaxosmithkline Llc Processus permettant de préparer des dérivés et des produits intermédiaires de carbamoylpyridone
US20160067255A1 (en) * 2014-09-04 2016-03-10 Gilead Sciences, Inc. Methods of treating or preventing hiv in patients using a combination of tenofovir alafenamide and dolutegravir

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
"Highleyman ''Cabotegravir and rilpivirine effective for HIV maintenance therapy at 96 weeks", NAM AIDSMAP, 19 March 2015 (2015-03-19), XP055442721, Retrieved from the Internet <URL:http://www.aidsmap.com/Cabotegravir-and- rilpivirine-effective-for-HIV-maintenance-therapy-at-96-weeks/page/2954476> *
"View of NCT02720094 on 2016_03_24", CLINICALTRIALS.GOV, 24 March 2016 (2016-03-24), XP055442723, Retrieved from the Internet <URL:https://clinicaltrials.gov/archive/NCT02720094/2016_03_24> *

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN109568328A (zh) * 2017-09-29 2019-04-05 重庆药友制药有限责任公司 一种用于预防和治疗hiv感染的药物组合物
WO2022003598A1 (fr) * 2020-07-02 2022-01-06 Viiv Healthcare Company Procédé d'obtention d'une rémission virale du vih à l'aide d'agents antirétroviraux à action prolongée
WO2022125378A3 (fr) * 2020-12-07 2022-07-21 Viiv Healthcare Company Polythérapie

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